Macroautophagy, herein referred to as autophagy, is a highly conserved process for cellular degradation and recycling of cytosolic contents to maintain cellular homeostasis. Autophagy substrates are generally cellular organelles, long-lived proteins and aggregate-prone proteins. Due to its functionality to clear cytosolic contents, this highly conserved process has been shown to be a promising approach for treatment of diseases characterized by the formation of intracellular aggregates, such as aging of the brain and neurodegeneration.
Dysfunction in the autophagy-lysosome pathway (ALP) has been directly linked to neurodegenerative disorders. Recently, the transcription factor EB (TFEB) has been identified in Settembre, C., et. al., TFEB links autophagy to lysosomal biogenesis. Science, 2011. 332(6036): 1429-33, and Sardiello, M., et al., A gene network regulating lysosomal biogenesis and function. Science, 2009. 325(5939): 473-7, as a master regulator of ALP. TFEB transgene to increase TFEB expression, or small molecules aimed to stimulate nuclear translocation of endogenous TFEB promotes the clearance of toxic protein aggregates, thus providing a disease-modifying intervention for neurodegenerative disorders such as Parkinson's disease (PD), Alzheimer's disease (AD) and Huntington's disease (HD).
Current MTOR inhibitors, such as rapamycin and torin1, activate TFEB by promoting TFEB nuclear translocation. However, their pharmacokinetic profile and side effects make them less likely to be useful for long-term use in patients with neurodegenerative diseases. Disaccharides, such as trehalose and sucrose, activate TFEB in an MTOR-independent manner and may be beneficial for neurodegenerative diseases. However, the blood-brain barrier (BBB) permeability of trehalose and sucrose is poor. Discovery of small molecules which directly target TFEB hold great promise for the development of efficient neuroprotective therapies.
It is an objective of the current invention to provide for a small molecule compound having good BBB permeability and potent TFEB-activating effects for the treatment of neurodegenerative diseases. The present invention provides a compound having simple chemical structure which can be easily synthesized in large scale. The present invention provides a compound that directly binds to and activates TFEB without inhibiting MTOR pathway, thus eliminating possible MTOR-associated complications. A further objective of the current invention is to provide a method for treating lysosomal storage disorders and diseases that can benefit from autophagy, including but not limited to neurodegenerative disorders, immunological diseases, cardiac diseases and cancer.